EP0172083B1 - Substituted amides, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The invention provides novel substituted amides of formula: R-CONH-Het in which R is cycloalkyl, cyclohexadienyl, phenyl optionally substituted with one or 2 fluorine atoms or with a hydroxy radical, or substituted at position 3- or 4- with an alkyl or alkyloxy radical, or with a methylenedioxy radical at positions 3- and 4-, or at position 2- or 3- with a dialkylamino radical, or is 3-pyridyl, alkyloxy-3-pyridyl, thienyl, alkylthienyl, furyl, tetrahydropyridyl, pyridazinyl and alkylpyridazinyl, and Het is 2-quinolyl or 1,8-naphthyridin-2-yl, both optionally substituted at position 7- with a halogen atom or a hydroxymethyl, alkyl, alkyloxy, alkyloxyalkyloxy, alkenyloxy or alkynyloxy radical (of 3 or 4 carbon atoms), an alkylthio or benzylthio radical, a phenoxy radical which is optionally substituted (with fluorine, with chlorine or bromine at position 2-, or with an alkyloxy radical or 1 or 2 alkyl radicals) or with pyridyloxy or alkylpiperidyloxy, provided that, when Het is 2-quinolyl, R is other than phenyl, and that the radicals and alkyl portions contain 1 to 4 carbon atoms each in a linear or branched chain. The new products are useful as anxiolytics, hypnotics, anticonvulsants, antiepileptics and muscle relaxants. The invention also provides a process for the preparation of, and pharmaceutical compositions containing, the new compounds.

Description

• - des procédés pour la préparation de N-(quinolyl-2) benzamide et son oxyde: M.A. Solekhova et Yu.V. Kurbatov Fiz. Khim. Issled. Sintetich. i Prirod Soedin., Samarkand, 10-16 (1980) [C.A. 96 142 655y], M.A. Solekhova et Yu. V. Kurbatov, Zh. Org. Khim., 17 (5),1121 (1981) [C.A. 95187 028s] et Tamara et coll. Chem. Pharm. Bull., 19(6), 1285-6 (1971),
• - des dérivés de benzamides utiles comme antiarythmiques de formule généralé:
  
  demande de brevet PCT 8 400 489,
• - des dérivés de naphthyridines-1,8 utiles comme bronchodilatateurs et vasodilatateurs périphériques ou comme agents hypotenseurs, de structure:
  
  demande de brevet néerlandais 7 305 482 et brevet américain 3 993 656.

In the literature have been described:

• - processes for the preparation of N- (quinolyl-2) benzamide and its oxide: MA Solekhova and Yu.V. Kurbatov Fiz. Khim. Issled. Sintetich. i Prirod Soedin., Samarkand, 10-16 (1980) [CA 96 142 655y], MA Solekhova and Yu. V. Kurbatov, Zh. Org. Khim., 17 (5), 1121 (1981) [CA 95187 028s] and Tamara et al. Chem. Pharm. Bull., 19 (6), 1285-6 (1971),
• - benzamide derivatives useful as antiarrhythmics of general formula:
  
  PCT patent application 8 400 489,
• - derivatives of 1,8-naphthyridines useful as bronchodilators and peripheral vasodilators or as hypotensive agents, of structure:
  
  Dutch patent application 7,305,482 and American patent 3,993,656.

leur préparation et les compositions pharmaceutiques qui les contiennent.The present invention relates to new substituted amides corresponding to the general formula:

their preparation and the pharmaceutical compositions containing them.

In the general formula (1), the symbol R represents a cycloalkyl radical containing 3 to 6 carbon atoms, cyclohexadienyl, phenyl, phenyl substituted by 1 or 2 fluorine atoms or by a hydroxy radical, or substituted in position -3 or - 4 by an alkyl or alkyloxy radical, or in positions -3 and -4 by a methylenedioxy radical, or substituted in position -2 or -3 by a dialkoylamino radical, or else the symbol R represents a heterocyclyl radical chosen from pyridyl-3, 3-alkyloxypyridyl, thienyl, alkylthienyl, furyl, tetrahydropyridyl, pyridazinyl and alkylpyridazinyl, and the symbol Het represents a quinolyl-2 or naphthyridine-1,8 yl-2 radical optionally substituted in position -7 by a halogen atom, by a hydroxymethyl radical, by an alkyl, alkyloxy, alkyloxyalkyloxy radical, by an alkenyloxy or alkynyloxy radical containing 3 or 4 carbon atoms, by an alkylthio or benzylthio radical, by a phenoxy radical (optionally substituted by a a fluorine or substituted by a chlorine or bromine atom in position -2, or substituted by an alkyl radical or by 1 or 2 alkyl radicals) or by a pyridyloxy or alkylpiperidyloxy radical, it being understood that, when Het represents a quinolyl radical -2, R is other than phenyl and that the radicals or alkyl portions mentioned above are straight or branched and contain 1 to 4 carbon atoms.

When the symbol Het contains a halogen substituent, the latter is chosen from fluorine, chlorine and bromine.

dans laquelle R est défini comme précédemment, ou d'un dérivé réactif de cet acide, sur une amine de formule générale:

dans laquelle Het est défini comme précédemment.According to the invention, the products of general formula (1) can be prepared by the action of an acid of general formula:

in which R is defined as above, or of a reactive derivative of this acid, on an amine of general formula:

in which Het is defined as above.

It is understood that, when the acid of general formula (II) contains a hydroxy radical, the latter is protected beforehand, by any known method which does not alter the rest of the molecule. For example, it is in particular protected by an acetyl radical which can be eliminated by treatment in basic medium, for example by treatment with ethanolic potassium hydroxide.

Similarly when in the amine of general formula (III) the symbol Het contains a hydroxyalkyl substituent it is preferable to protect the hydroxy radical before the reaction. The protection is carried out by any method known per se which does not alter the rest of the molecule, in particular by means of a tetrahydropyrannyl radical which can be easily removed by acidolysis in an aqueous medium.

When the acid of general formula (II) is used, the operation is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example dicyciohexyicarbodiimide) or N, N'-carbonyldiimidazole or the 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, in an organic solvent such as an ether (e.g. tetrahydrofuran, dioxane, glyme, diglyme), an amide (e.g. dimethylformamide), a nitrile (e.g. acetonitrile) or a chlorinated solvent (for example methylene chloride, dichloroethane or chloroform) at a temperature between 0 ° C and the reflux temperature of the reaction mixture. Preferably one operates at 20 ° C.

When using a reactive acid derivative of general formula (II) it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester [which can be chosen from esters activated or not activated acid of general formula (II) 1. The operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as an organic nitrogenous base (for example a tri- alkyllamine, pyridine, diaza-1,8 bicyclo [5.4.01 undecene-7 or diaza-1,5 bicyclo [4.3.0] nonene-5), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between 0 ° C. and the reflux temperature of the reaction mixture, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline-earth base (soda, potash) or of a carbonate or bicarbonate of '' an alkaline or alkaline earth metal at a temperature between 0 and 40 ° C. It is also possible to operate without solvents at the melting temperature of the reaction mixture.

According to the invention, the products of general formula (1) in which the symbol Het contains a hydroxymethyl substituent can also be prepared by reduction of the corresponding aldehyde.

The reduction is advantageously carried out by the action of sodium borohydride or by catalytic hydrogenation in the presence of nickel, platinum or palladium in an organic or hydroorganic medium, for example in an alcohol (methanol, ethanol) in an ether (tetrahydrofuran, dioxane) or in a mixture of these solvents at a temperature between 0 and 50 ° C. The starting aldehyde can be prepared by oxidation of a product of general formula (1) in which Het contains a methyl substituent. The reaction is carried out by means of an oxidizing agent such as selenium oxide, in an organic solvent such as dioxane at the reflux temperature of the reaction mixture.

• - H.D. HARTOUGH, the Chemistry of heterocyclic compounds, thiophen and its derivatives, Interscience Publishers Inc. New-York, page 363 (1952);
• - J.W. MASON, The Chemistry of heterocyclic compounds, Pyridazine carboxylic acids, John Wiley and Sons Inc. New-York, page 407 (1973);
• - E.P. OLIVETO, The Chemistry of heterocyclic compounds Pyridine-carboxylic acids, Interscience Publishers Inc., page 179 (1962).
• - A.A. PETROV. et coll., Zhur Obshchei Khim, 26,1958 (1956), M.E. KUEHNE et coll., Org. Synth., 43,22 (1968), S. Hunig et coll., Chem. Ber., 90, 238 (1957) ou H. Plieninger et coll., Chem. Ber., 94, 2088 (1961) lorsqu'il s'agit d'un acide cyclohexa- diénylcarboxylique.

The acids of general formula (II) can be prepared by applying the methods below (or by analogy with these methods):

• - HD HARTOUGH, the Chemistry of heterocyclic compounds, thiophen and its derivatives, Interscience Publishers Inc. New-York, page 363 (1952);
• - JW MASON, The Chemistry of heterocyclic compounds, Pyridazine carboxylic acids, John Wiley and Sons Inc. New-York, page 407 (1973);
• - EP OLIVETO, The Chemistry of heterocyclic compounds Pyridine-carboxylic acids, Interscience Publishers Inc., page 179 (1962).
• - AA PETROV. et al., Zhur Obshchei Khim, 26,1958 (1956), ME KUEHNE et al., Org. Synth., 43.22 (1968), S. Hunig et al., Chem. Ber., 90, 238 (1957) or H. Plieninger et al., Chem. Ber., 94, 2088 (1961) when it is a cyclohexadienylcarboxylic acid.

[dans lesquelles R' représente un radical alcoyle, alcoyloxyalcoyle, alcényle, alcynyle, phényle éventuellement substitué (par un atome de fluor, par un atome de chlore ou de brome en position -2, par un radical alcoyloxy, ou par un ou 2 radicaux alcoyle), ou un radical pyridyle ou alcoylpipéridyle et R" représente un radical alcoyle ou benzylel, en milieu basique, ou par action de l'alcoolate ou du thiolate correspondant.The amines of general formula (III) in which the symbol Het carries an alkyl, alkoxyalkoxy, alkenyloxy, alkynyloxy or optionally substituted phenoxy substituent, a pyridyloxy or alkylpiperidyloxy substituent, or an alkyloylio or benzylthio substituent, can be prepared from amine correspondent in which the symbol Het carries a halogen substituent (preferably a chlorine atom) by the action respectively of a hydroxylated derivative or of a thiol of general formulas:

[in which R 'represents an alkyl, alkyloxyalkyl, alkenyl, alkynyl, phenyl radical optionally substituted (by a fluorine atom, by a chlorine or bromine atom in position -2, by an alkyloxy radical, or by one or 2 radicals alkyl), or a pyridyl or alkylpiperidyl radical and R "represents an alkyl or benzylel radical, in basic medium, or by the action of the corresponding alcoholate or thiolate.

The reaction is generally carried out in the presence of a strong base (sodium hydroxide, potash, quaternary ammonium hydroxide, sodium ethylate for example), at a temperature between 50 and 150 ° C, or else in the presence of the alcoholate or corresponding thiolate (for example sodium alcoholate), in a solvent such as an amide (for example dimethylformamide) or an ether (for example tetrahydrofuran, dimethoxyethane), or without solvent, in the presence of an excess of hydroxylated or thiol derivative, at a temperature between 70 ° C. and the reflux temperature of the reaction mixture.

When the alcoholate or thiolate is used, it is obtained beforehand by the action of sodium on the alcohol of general formula (IVa) or the thiol of general formula (IVb) at a temperature between 20 and 80 ° C, or by the action of sodium hydride at a temperature between 0 and 20 ° C in a solvent such as dimethylformamide, dimethoxyethane, or tetrahydrofuran. It is not necessary to isolate the alcoholate or the thiolate obtained in order to use it in the following reaction.

The amines of general formula (III) in which the symbol Het contains a hydroxymethyl substituent can be obtained by reduction of the corresponding aldehyde whose amine function has been previously protected (for example by a benzyl radical). The reaction is carried out under the conditions described above for the preparation of a product of general formula (I) in which the symbol Het carries a hydroxymethyl substituent. The starting aldehyle can be prepared by analogy with the preparation of the raw material in the above process.

• - S. CARBONI, Gazz. Chim. Italiana, 96, 1456 (1966);
• - E.V. BROWN, J. Org. Chem., 30, 1607 (1965);
• - G. JONES, The Chemistry of Heterocyclic compounds, Quinoiins, John Wiley and Sons Inc., New-York, Part 1 (1977), Part Il (1982)
• - ou selon les brevets américains 3 948 917 et 3884921.

The amines of general formula (III) can also be prepared by application of the methods described below in the examples or by application or by analogy with the methods described by:

• - S. CARBONI, Gazz. Chim. Italiana, 96, 1456 (1966);
• - EV BROWN, J. Org. Chem., 30, 1607 (1965);
• - G. JONES, The Chemistry of Heterocyclic compounds, Quinoiins, John Wiley and Sons Inc., New-York, Part 1 (1977), Part Il (1982)
• - or according to American patents 3,948,917 and 3,849,921.

dans laquelle Het est défini comme précédemment.According to the invention, the products of general formula (1) in which the symbol R is a tetrahydroxypyridyl radical can be prepared by the action of tetrahydropyridine on a carbamate of general formula:

in which Het is defined as above.

The reaction usually takes place in soil organic compound such as a nitrile (acetonitrile for example) or an ether (tetrahydrofuran for example) or in a mixture of these solvents, at a temperature between 60 ° C. and the reflux temperature of the reaction mixture.

The carbamate of general formula (V) can be obtained by the action of an amine of general formula (III) on the corresponding chloroformate.

It is generally carried out in pyridine at a temperature between 0 and 40 ° C. in the presence of an acid acceptor such as pyridine or a trialkylamine (triethylamine for example) optionally in an organic solvent such as tetrahydrofuran.

The new amides according to the present invention can be purified if necessary, by physical methods such as crystallization or chromatography.

The products of general formula (1) have particularly advantageous pharmacological properties. They show activity as anxiolytics, hypnotics, anticonvulsants, antiepileptics and muscle relaxants of good level, highlighted in the tests below.

In particular, they have a good in vitro affinity for benzodiazepine receptor sites at concentrations between 5 and values close to 1000 nM according to the technique described by JC Blanchard and L. Julou, J. of Neurochemistry, 40, 601 (1983) inspired by the work of Squires and Braestrup, Nature, 266, 732 (1977);

In animals (mice) they have been shown to be active at doses of between 10 and about 200 mg / kg orally with respect to convulsions induced by pentetrazol according to a technique similar to that of Everett and Richards, J Pharmacol., 81, 402 (1944).

Furthermore, the products of general formula (1) in which R is a phenyl radical substituted in position -3 or -4 by an alkyl radical or in position -3 and -4 by a methylenedioxy radical and Het is a naphthyridine-1 radical, 8 yle-2 substituted in position -7 by a radical as defined in general formula (I), or else R is a phenyl radical and Het is a naphthyridine-1,8 yl-2 radical substituted in position -7 by a hydroxymethyl, alkyl or benzylthio radical or with a substituted phenoxy radical, as defined in general formula (1), or a pyridyloxy or alkylpiperidyloxy radical, or else R is a methoxyphenyl radical and Het is a naphthyridine-1,8 yl radical- 2 substituted in position -7 by a bromine atom or by a hydroxymethyl, benzylthio or phenoxy radical, exhibit an immunostimulatory activity.

The immunostimulating activity has been demonstrated in vitro at molar concentrations between 10- ⁵ and 10- ⁶ in stimulating the acti vity cytostatic peritoneal macrophages of the mice vis-à-vis the tumor cells ₈₁ P ₅ according to a technique inspired by MIC Gyôngyôssi et al., Cell. Immunol., 45, 1 (1979), and in vivo in mice, they stimulate defense reactions against Klebsiella pneumoniae infection at doses between 2 and 20 mg / kg ip according to a technique inspired by MA Parant and coll., Infect. Immun., 27, 826 (1980).

An advantage of the immunostimulatory activity of the products is their use as an anti-infectious agent, having in particular the possibility of fighting against germs which have become resistant to traditional antibiotics.

Furthermore, the products of general formula (I) in which the symbol R represents a 4-methoxy-phenyl, 3-thienyl or 5-methyl-thienyl radical and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position -7 with a chlorine atom, a methoxy or hydroxymethyl radical or in which the symbol R represents a thienyl-2 radical and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position -7 by a methoxy radical or phenoxy also exhibit antiviral activity.

The antiviral activity has been demonstrated in vitro on influenza A and B viruses at concentrations between 1.5 and 30 _Il g / cm ³ .

In addition, these products exert in vivo significant protective activity against influenza infection (A ₂ Am Arbor) in mice, at doses between 30 and 300 mg / kg orally.

Furthermore, the products according to the invention have low toxicity: their LD ₅₀ orally in mice is between 300 and 900 mg / kg and doses greater than 900 mg / kg.

Of particular interest are the products of general formula (1) for which the symbol R is a cyclopropyl or cyclobutyl, cxclohexadiene-1,4-yl-1, phenyl, phenyl substituted by one or 2 fluorine atoms, or by a hydroxy radical, or substituted in position -3 or -4 by an alkyl radical containing 1 or 2 carbon atoms, or an alkyloxy radical containing 1 to 4 carbon atoms, or in positions -3 and -4 by a methylenedioxy radical or substituted by a dimethylamino radical in position -3, or else the symbol R is a heterocyclyl radical chosen from pyridyl-3, 6-alkyl-pyridyl-3, thienyl, 5-alkyl thienyl, furyl, pyridazinyl-3 or 6-alkyl pyridazinyl-3 the alkyl portions of which contain 1 or 2 carbon atoms, and the symbol Het represents a quinolyl-2 or naphthyridine-1,8 yl-2 radical optionally substituted in position -7 by a halogen atom, by a hydroxymethyl radical, by an alkyl or alkylthio radical containing 1 or 2 carbon atoms e, by an alkyloxy radical containing 1 to 4 carbon atoms or an alkyloxyalkoyloxy containing 2 to 4 carbon atoms, by an allyloxy, propargyloxy or benzylthio radical, by a phenoxy radical, substituted phenoxy (by a fluorine atom or by a chlorine or bromine in position -2, by an alkyloxy radical or by 1 or 2 alkyl radicals containing 1 or 2 carbon atoms) or by a pyridyl-3 oxy or alkyl-1 piperidyl-4 oxy radical, it being understood that when Het represents a quinolyl-2 radical, R is other than phenyl.

And among these products, more especially active, are the products of general formula (1) in which the symbol R is a cyclopropyl, cyclohexadiene-1,4-yl, phenyl, phenyl radical substituted by 1 or 2 fluorine atoms or by a radical hydroxy, or substituted in position -3 or -4 by an alkyloxy radical containing 1 or 2 carbon atoms or in positions -3 and -4 by a methylenedioxy radical, or substituted in position -3 by a dimethylamino radical, or else the symbol R is a heterocyclyl radical chosen from pyridyl-3, 6-alkyl-pyridyl-3, the alkyl portion of which contains 1 or 2 carbon atoms, thienyl or furyl and the symbol Het represents a naphthyridine-1,8 yl-2 radical optionally substituted in position -7 by a halogen atom by an alkyl, alkyloxy or alkylthio radical containing 1 or 2 atoms carbon, by an alkyloxyalkoyloxy radical containing 2 to 4 carbon atoms, by an allyloxy or phenoxy radical (optionally substituted by a fluorine atom, or by a chlorine or bromine atom in position -2, by an alkyloxy radical or by 1 or 2 alkyl radicals containing 1 or 2 carbon atoms), or by a 3-pyridyl oxy radical.

• - N-(méthoxy-7 naphtyridine-1,8 yl-2) cyclopropanecarboxamide
• - N-(chloro-7 naphtyridine-1,8 yl-2) fluoro-4 benzamide
• - N-(bromo-7 naphtyridine-1,8 yl-2) méthoxy-4 benzamide
• - N-(méthoxy-7 naphtyridine-1,8 yl-2) méthoxy-4 benzamide
• - N-(méthoxy-7 naphtyridine-1,8 yl-2) thiophènecarboxamide-2.

In particular, more particularly remarkable are the products of general formula (1) in which the symbol R is a cyclopropyl, phenyl or phenyl radical substituted in position -3 or -4 by a fluorine atom, or substituted by 2 fluorine atoms or by a hydroxy radical, or substituted in position -3 or -4 by a methoxy radical, or else the symbol R is a heterocyclyl radical chosen from 6-alkyloxy-pyridyl in which the acloyl portion contains 1 or 2 carbon atoms, 2-thienyl or furyl -3, and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position -7 by a halogen atom, by a methoxy radical or by a phenoxy radical (optionally substituted by a fluorine atom or in position -2 by a chlorine atom or a methyl radical, or in position -2 or -3 by a methoxy radical), or the symbol R represents a cyclohexadiene-1,4-yl-1, phenyl radical (substituted in positions -3 and -4 by a methylenedioxy radical or substituted in position -3 by a radical dimethylamino) or a pyridyl-3 radical and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position -7 by a halogen atom and among these the following products:

• - N- (7-methoxy-naphthyridine-1,8 yl-2) cyclopropanecarboxamide
• - N- (chloro-7 naphthyridine-1,8 yl-2) fluoro-4 benzamide
• - N- (bromo-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide
• - N- (7-methoxy-naphthyridine-1,8 yl-2) 4-methoxy benzamide
• - N- (7-methoxy-naphthyridine-1,8 yl-2) thiophenecarboxamide-2.

The following examples illustrate the present invention:

Example 1

To a solution of 10.9 g of acid p. toluic in 100 cm ³ of anhydrous tetrahydrofuran, 12.9 g of N, N'-carbonyidiimidazole are added. An immediate gas evolution is observed. The mixture is stirred for 1 hour at a temperature in the region of 20 ° C, until the end of gas evolution. 8.9 g of 2-amino-7-chloro-naphthyridine-1.8 are then added and the mixture is heated at reflux for 20 hours. The mixture is poured into 1000 cm ³ of distilled water, the precipitate formed is separated by filtration, washed with water and air dried.

The product obtained (13.6 g; M = 222 ° C) is dissolved in 470 cm ³ of boiling ethanol. After 4 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 10 of N- (7-chloro-naphthyridine-1,8 yl-2) -4-methyl benzamide are obtained, melting at 228 ° C.

Example 2

The procedure is analogous to that described in Example 1, but starting with 5.2 g of cyclopropylcarboxylic acid, 9.8 g of N, N'-carbonyl-diimidazole and 7.2 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (10 g; M = 250 ° C) is dissolved in 530 cm ³ of boiling 2-propanol.

After 4 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of propanol-2 and dried at 40 ° C under reduced pressure (0.067 kPa). 7.5 g of N- (7-chloro-naphthyridine-1,8 yl-2) cyclopropanecarboxamide, melting at 250 ° C., are obtained.

Example 3

The procedure is analogous to that described in Example 1, but starting with 13.7 g of cyclopropanecarboxylic acid, 25.8 g of N, N'-carbonyldiimidazole and 17.5 g of 2-amino-7-methoxy-naphthyridine-1,8. The product obtained by precipitation in water (24.3 g; M = 100 ° C) is purified by chromatography on a column 40 mm in diameter containing 400 g of silica (0.040 - 0.063 mm), eluting with a mixture (95 -5 by volume) of methylene chloride and methanol and collecting 100 cm ³ fractions. After dry concentration of fractions 6 to 17 at 40 ° C under reduced pressure (4 kPa), 17 g of a solid melting at 170 ° C are obtained. This product is dissolved in 120 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 12.5 g of N- (7-methoxy-naphthyridine-1,8 yl-2) cyclopropanecarboxamide, melting at 170 ° C., are obtained.

Amino-2-methoxy-7 naphthyridine-1,8 can be prepared according to the method described in US Patent 3,948,917.

Example 4

The procedure is analogous to that described in Example 1, but starting with 4.8 g of cyclopropane carboxylic acid, 9.07 g of N, N'-carbonyl-diimidazole and 10 g of 2-amino-7-phenoxy-naphthyridine-1,8. The product obtained by precipitation in water (11.2 g; mp approximately 170 ° C) is dissolved in 200 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 6.4 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) cyclopropanecarboxamide, melting at 190 ° C., are obtained.

Amino-2 phenoxy-7 naphthyridine-1,8 can be prepared as follows:

A mixture composed of 27 g of 2-chloro-7 amino is heated for 20 hours at 120 ° C. naphthyridine-1,8, 141 g of phenol and 19.8 g of potassium hydroxide pellets at 85%. The mixture obtained is taken up in 300 cm ³ of an aqueous 4N sodium hydroxide solution and extracted with 250 cm ³ of methylene chloride.

The aqueous phase is extracted again with 2 times 200 cm ³ of methylene chloride. The organic extracts are washed with 2 times 150 cm ³ of 4N sodium hydroxide then 250 cm ³ of distilled water, dried over magnesium sulfate and concentrated to dryness at 40 ° C under reduced pressure (4 kPa).

The product obtained (30.5 g; mp 190-194 ° C) is dissolved in 400 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 20 cm ³ of acetonitrile and dried at 45 ° C, under reduced pressure (0.067 kPa). 23.4 g of amino-2 phenoxy-7 naphthyridine-1,8 are obtained, melting at 196 ° C.

Example 5

The procedure is analogous to that described in Example 1, but starting with 5 g of cyclobutane carboxylic acid, 10.5 g of N, N'-carbonyidiimidazole and 7 g of 2-chloro-amino -7 naphthyridine-1.8. The product obtained by filtration (9 g; M = 192 ° C) is dissolved in 150 cm ³ of boiling acetonitrile. After 3 hours of cooling to 20 ° C, the crystallized solid is separated by filtration, washed with 3 times 25 cm ³ of ethyl ether and dried at 35 ° C under reduced pressure (0.066 kPa). 6.3 g of N- (chloro-7 naphthyridine-1, 8 yl-2) cyclobutanecarboxamide, melting at 192-194 ° C., are obtained.

Example 6

The procedure is analogous to that described in Example 1, but starting with 6.2 g of 1,4-cyclohexadiene-1,4-carboxylic acid, 8 g of N, N'-carbonyldiimidazole and 8 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (11 g; M = 205 ° C) is dissolved in 250 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 15 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 4.2 g of N- (7-chloro-naphthyridine-1,8 yl-2) cyclohexadiene-1,4 carboxamide-1 are obtained, melting at 210 ° C.

Cyclohexadiene-1,4-carboxylic-1 acid can be prepared according to the method described by A.A. Petrov. et al., Zhur Obshchei Khim, 26, (1956) [C.A. 51 1887th (1957)].

Example 7

The procedure is analogous to that described in Example 1, but starting with 12.4 g of 1,4-cyclohexadiene-1,4-carboxylic acid, 16.2 g of N, N'-carbonyldiimidazole and 21.4 g of amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (17.2 g; M = 95 ° C) is dissolved in 150 cm ³ of boiling methanol. After 3 hours of cooling to 20 ° C, the crystallized solid is separated by filtration, washed with 3 times 15 cm ³ of methanol and dried at 40 ° C under reduced pressure (0.067 kPa). 13.2 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) cyclohexadiene-1,4 carboxamide-1 are obtained, melting at 95 ° C.

Example 8

To a solution of 5.4 g of 2-amino-7-chloro-naphthyridine-1,8 in 60 cm ³ of pyridine, 4.2 g of benzoyl chloride is slowly added while maintaining the temperature in the region of 30 ° C. After maintaining the solution for 3 hours at a temperature in the region of 20 ° C, the product is precipitated from 340 cm ³ of distilled water. The solid obtained after air drying is dissolved in 88 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 4.95 g of N- (7-chloro-naphthyridine-1,8 yl-2) benzamide are thus obtained, melting at 198 ° C.

Example 9

The procedure is analogous to that described in Example 1, but starting with 13.4 g of benzoic acid, 17.8 g of N, N'-carbonyldiimidazole and 12.3 g of amino -2-7-methoxy-naphthyridine-1,8. The product obtained by precipitation in water (20 g; mp = 80 ° C) is dissolved in 200 cm ³ of boiling acetonitrile. After 1 hour of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 7.8 g of N- (7-methoxy-naphthyridine-1,8 yl-2) benzamide are obtained, melting at 134 ° C.

Example 10

The procedure is analogous to that described in Example 1, but starting from 8.9 g of benzoic acid, 11.8 g of N, N'-carbonyldiimidazole and 15 g of 2-amino-benzylthio -7 naphthyridine-1.8. The product obtained by precipitation in water (25 g; mp about 120 ° C.) is purified by chromatography on a column 5 cm in diameter containing 600 g of silica (0.063 - 0.2 mm), eluting with methylene. Fractions of 100 cm ^{3 are} collected, fractions 14 to 56 are concentrated to dryness under reduced pressure (4 kPa) to give 22.4 g of a solid, melting at 142-144 ° C. This product is dissolved in 250 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 25 cm ³ of ethanol and dried at 40 under reduced pressure (0.067 kPa). 19 g of N- (7-benzylthio-naphthyridine-1,8 yl-2) benzamide are obtained, melting at 144-145 ° C.

Amino-2 benzylthio-7 naphthyridine-1,8 can be prepared as follows:

To a sodium ethylate solution prepared from 2.3 g of sodium and 160 cm ³ of ethanol, 13.6 g of benzylmercaptan are added and the mixture is stirred for 1 hour at a temperature in the region of 20 ° C. 18 g of amino-2-chloro-7 naphthyridine-1,8 are then added and the mixture is heated for 6 hours at 60 ° C. The suspension obtained is poured into 500 cm ³ of water and extracted with 3 times 250 cm ³ of methylene chloride. After washing with water and drying, the organic solution is concentrated to dryness under reduced pressure (4 kPa) to give 15.4 g of 2-amino-7-benzylthio-naphthyridine-1,8, melting at 167 ° C.

Example 11

To a solution of 6.8 g of benzoic acid in 180 cm ³ of anhydrous tetrahydrofuran, 9.1 g of N, N'-carbonyldiimidazole are added. An immediate gas evolution is observed. The mixture is stirred for 2 hours at a temperature in the region of 20 ° C., until the end of gas evolution. 10 g of amino-2 phenoxy-7 naphthyridine-1,8 are then added and the mixture is heated at reflux for 18 hours.

The mixture is poured into 800 cm ³ of distilled water; the precipitate formed is separated by filtration, washed with water and air-dried.

The product obtained (14 g; M = 169 ° C) is dissolved in 160 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 8 cm ³ of acetonitrile and dried at 25 ° C under reduced pressure (0.067 kPa). 8 g of N- (phenoxy-7 naphthyridine - 1.8 yl-2) benzamide are obtained, melting at 170 ° C.

Example 12

The procedure is analogous to that described in Example 1, but starting with 11 g of benzoic acid, 16.2 g of N, N'-carbonyldiimidazole and 26.7 g of 2-amino (4-methoxy phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (30.8 g; mp about 110 ° C.) is dissolved in 150 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of acetonitrile and dried at 50 ° C under reduced pressure (0.067 kPa). 24.7 g of N - [(4-methoxy phenoxy) -7 naphthyridin-1,8 yl-2] benzamide are obtained, melting at 171 ° C.

Amino-2 (4-methoxy phenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting with 35.8 g of 2-amino-7-chloro-naphthyridin-1,8, 99.2 g of 4-methoxyphenol and 22 , 4 g of potash in 85% tablets. After treatment with sodium hydroxide and washing, 52.9 g of amino-2 (4-methoxy-phenoxy) -7 naphthyridine-1,8, melting at 200 ° C., are obtained.

Example 13

The procedure is analogous to that described in Example 1, but starting with 11.2 g of 2-fluoro benzoic acid, 12.9 g of N, N'-carbonyldiimidazole and 8.9 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (13.6 g; M = 218 ° C) is dissolved in 450 cm ³ of boiling propanol-1. After 3 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of propanol-1 and dried at 40 ° C under reduced pressure (0.067 kPa). 8.3 g of N- (7-chloro-naphthyridine-1,8 yl-2) fluoro-2 benzamide are obtained, melting at 222 ° C.

Example 14

The procedure is analogous to that described in Example 1, but starting with 20 g of 3-fluoro benzoic acid, 23 g of N, N'-carbonyldiimidazole and 16.9 g of amino- 2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (25 g; M = 201 ° C) is dissolved in 230 cm ³ of boiling acetonitrile. After 4 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 20 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 21.4 g of N- (7-chloro-naphthyridine-1,8 yl-2) fluoro-3 benzamide are obtained, melting at 202 ° C.

Example 15

The procedure is analogous to that described in Example 1, but starting with 11.2 g of 4-fluoro benzoic acid, 12.9 g of N, N'-carbonyldiimidazole and 8.9 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (14.3 g; M = 230 ° C) is dissolved in 800 cm ³ of boiling 2-propanol. After 4 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of propanol-2 and dried at 40 ° C under reduced pressure (0.067 kPa). 10.3 g of N- (chloro-7 naphthyridine-1,8 yl-2) fluoro-4 benzamide are obtained, melting at 236 ° C.

Example 16

The procedure is analogous to that described in Example 1, but starting with 15.4 g of 4-fluoro benzoic acid, 17.8 g of N, N'-carbonyldiimidazole and 15.7 g amino-2 bromo-7 naphthyridine-1,8. The product obtained by precipitation in water (26.2 g; mp = 226 ° C) is purified by filtration on a column 45 mm in diameter containing 300 g of silica (0.040 - 0.063 mm), eluting with pure dichloromethane and collecting 100 cm ³ fractions. After dry concentration of fractions 10 to 70 to 40 ° C under reduced pressure (4 kPa), 18.5 g of a solid melting at 228 ° C are obtained. This product is dissolved in 600 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 13.1 g of N- (7-bromo-naphthyridine-1,8 yl-2) fluoro-4 benzamide are obtained, melting at 228 ° C.

Example 17

The procedure is analogous to that described in Example 1, but starting with 12.1 g of 2,6-difluoro-benzoic acid, 12.3 g of N-N'-carbo-nyldiimidazole and 8.5 g of amino-2-chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (6.8 g; M = 215 ° C) is dissolved in 450 cm ³ of boiling ethanol. After 4 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 15 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 7.3 g of N- (chloro-7 naphthyridine-1,8 yl-2) -difluoro-2,6 benzamide, melting at 242 ° C., are obtained.

Example 18

The procedure is analogous to that described in Example 1, but starting with 5.1 g of 2,6-difluoro-benzoic acid, 5.2 g of N, N'-carbonyidiimidazole and 4.4 g of 2-amino-7-methoxy-naphthyridine-1,8. The product obtained by precipitation in water (4.5 g; M = 215-217 ° C) is dissolved in 70 cm ³ of boiling ethanol. After cooling for 1 hour at 4 ° C., the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at at 45 ° C under reduced pressure (0.067 kPa). 3.2 g of N- (7-methoxy-naphthyridine-1,8 yl-2-difluoro-2,6 benzamide, melting at 219-220 ° C., are obtained.

Example 19

To a solution of 3.5 g of 2-amino-7-methoxy-naphthyridine in 40 cm ³ of pyridine, 4.4 g of 3-acetoyenzoyl chloride are added. The mixture is stirred for 1 hour 30 minutes at a temperature in the region of 25 ° C. The suspension obtained is taken up in 400 cm ³ of distilled water and the precipitate obtained is air dried to give 6.6 g of a solid, melting at 172 ° C. This product is dissolved in 140 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of ethanol and dried at 50 ° C under reduced pressure (0.067 kPa). 5.3 g of N- (7-methoxy-naphthyridine-1,8 yl-2) acetoxy-3 benzamide are obtained, melting at 172 ° C. 12 g of N- (7-methoxy-naphthyridine-1,8 yl-2) acetoxy-3 benzamide obtained under the conditions described above are treated by heating at reflux for 15 minutes in 35 cm ³ of a 10% solution of ethanolic potash. The solid obtained after dilution with 250 cm ³ of water and acidified with 20 cm ³ of 4N hydrochloric acid is air dried to give 9.2 g of a solid melting at a temperature above 260 ° C. The product obtained is dissolved in 1500 cm ³ of boiling propanol-1. After reforidization for 4 hours at a temperature of 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 50 cm ³ of propanol-1 and dried at 60 ° C under reduced pressure (0.067 kPa). 6 g of N- (7-methoxy-naphthyridine-1,8 yl-2) hydroxy-3 benzamide are obtained, melting at 295 ° C.

Example 20

The procedure is analogous to that described in Example 1, but starting with 4.55 g of 4-methoxy benzoic acid, 6.55 g of N, N'-carbodiimidazole and 5.2 g 2-amino-naphthyridine-1,8. The product obtained by precipitation in water (8.35 g; MP = 85 ° C, pasty) is filtered, then dissolved in 50 cm ³ of boiling propanol-1. After 1 hour of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of propanol-1 and dried at 35 ° C under reduced pressure (0.067 kPa). 6.9 g of N- (naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 150 ° C. Amino-2 naphthyridine-1,8 can be prepared according to US Patent 3,948,917.

Example 21

The procedure is analogous to that described in Example 1, but starting with 12.17 g of 3-methoxy benzoic acid, 12.9 g of N, N'-carbonyl-diimidazole and 8.9 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (15.5 g; M = 176 ° C) is dissolved in 500 cm ³ of boiling 2-propanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 25 cm ³ of propanol-2 and dried at 40 ° C under reduced pressure (0.067 kPa). 11.2 g of N- (7-chloro-naphthyridine-1,8 yl-2) methoxy-3 benzamide are obtained, melting at 178 ° C.

Example 22

The procedure is analogous to that described in Example 1, but starting with 4.6 g of 4-methoxy benzoic acid, 4.9 g of N, N'-carbonyldiimidazole and 3.6 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (4.3 g; M = 208 ° C) is dissolved in 660 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of acetonitrile and dried at 50 ° C under reduced pressure (0.067 kPa). 3.5 g of N- (chloro-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 208 ° C.

Example 23

The procedure is analogous to that described in Example 1, but starting with 10.2 g of 4-methoxy benzoic acid, 10.8 g of N, N'-carbonyldiimidazole and 11.2 g amino-2 bromo-7 naphthyridine-1,8. The product obtained by precipitation in water (9.8 g; M = 220 ° C) is dissolved in 1000 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 8.3 g of N- (7-bromo-naphthyridin-1.8 yl-2) 4-methoxy-benzamide are obtained, melting at 221 ° C.

The amino-2 bromo-7 naphthyridine-1,8 can be prepared according to the method described by S. CARBONI, Gazz. Chim. Ital. 96, 1464 (1966).

Example 24

The procedure is analogous to that described in Example 1, but starting with 12.2 g of 4-methoxy benzoic acid, 10.3 g of N, N'-carbonyldiimidazole and 9.5 g amino-2 methyl-7 naphthyridine-1,8. The product obtained by precipitation in water (14.4 g; M = 110 ° C) is dissolved in 150 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 45 ° C under reduced pressure (0.067 kPa). 12.7 g of N- (7-methylnaphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 119 ° C.

The amino-2 methyl-7 naphthyridine-1,8 can be prepared according to the method described by E.V. BROWN, J. Org. Chem. 30, 1607 (1965).

Example 25

The procedure is analogous to that described in Example 1, but starting from 9.1 g of 3-methoxy benzoic acid, 9.7 g of N, N'-carbonyldiimidazole and 7 g of amino -2-7-methoxy-naphthyridine-1,8. The product obtained by precipitation in water (13 g; mp about 75 ° C) is dissolved in 90 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of acetonitrile and dried at 50 ° C. under reduced pressure (0.067 kPa). 8.7 g of N- (methoxy-7 naphthyridine-1,8 yl-2) methoxy-3 benzamide are obtained, melting at 135 ° C.

Example 26

The procedure is analogous to that described in Example 1, but starting with 13.2 g of acid 4-methoxy benzoic, 14.1 g of N, N'-carbonyldiimidazole and 11.5 g of 2-amino-7-methoxy-1,8-naphthyridine. The product obtained by precipitation in water is dried under reduced pressure (0.067 kPa) and purified by filtration on a column 5 cm in diameter loaded with 400 g of silica (0.063-0.2 mm), eluting with methylene.

100 cm ³ fractions are collected. Fractions 8 to 38 are combined and concentrated to dryness under reduced pressure (4 kPa). The product obtained is dissolved in 150 cm ³ of boiling acetonitrile. After 4 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa).

10.9 g of N- (7-methoxy-naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 115 ° C. Amino-2-methoxy-7 naphthyridine-1,8 can be prepared according to US Patent 3,948,917.

Example 27

The procedure is analogous to that described in Example 1, but starting with 19.8 g of 4-methoxy benzoic acid, 21.1 g of N, N'-carbonyldiimidazole and 18.5 g amino-2 ethoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (28.9 g; M = 144 ° C) is dissolved in 280 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 24 g of N- (7-ethoxy-naphthyridine-1,8 yl-2) methoxy-4 benzamide, melting at 152 ° C., are obtained.

Amino-2 ethoxy-7 naphthyridine-1,8 can be prepared according to the method described by S. CARBONI, Gazz. Chim. state. 96, 1456 (1966).

Example 28

The procedure is analogous to that described in Example 1, but starting with 16.7 g of 4-methoxy benzoic acid, 19.4 g of N, N'-carbonyldiimidazole and 25 g of 2-amino-isopropoxy-7 naphthyridine-1,8. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration to dryness under reduced pressure (4 kPa) the oil obtained (39 g) is stirred in the presence of 100 cm ³ of diethyl ether to give a crystallized solid (23 g; mp 78 ° C). The product obtained is dissolved in 100 cm ³ of boiling isopropyl oxide. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of diethyl ether and dried at 40 ° C. under reduced pressure (0.067 kPa). 12.9 g of N- (isopropoxy-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 82 ° C.

Amino-2 isoporpoxy-7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 29, but starting from 35.9 g of 2-amino-7-chloro-naphthyridine-1,8 of 150 cm ³ of propanol-2 and of 9.2 g of sodium. The excess propanol-2 is evaporated under reduced pressure (4 kPa) and the residue is taken up in distilled water to yield a crystallized solid (38.7 g; mp = 162 ° C). 11 g of the solid obtained are dissolved in 50 cm ³ of boiling ethyl acetate. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of diethyl ether and dried at 50 ° C. under reduced pressure (0.067 kPa). 6.9 g of amino-2 isopropoxy-7 naphthyridine-1,8 are obtained, melting at 170 ° C.

Example 29

The procedure is analogous to that described in Example 1, but starting with 5.8 g of 4-methoxy benzoic acid, 6.5 g of N, N'-carbonyldiimidazole and 8.5 g amino-2 (2-methoxy ethoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (8 g; M = pasty 75 ° C.) is putified by chromatography on a column 40 mm in diameter containing 250 g of silica (0.063 - 0.2 mm), eluting with a mixture (99.5 - 0.5 by volume) of methylene chloride and methanol. 100 cm ³ fractions are collected, fractions 12 to 31 are combined and concentrated to dryness under reduced pressure (4 kPa) at 40 ° C to give 10.3 g of a solid melting at 114 ° C. This product is dissolved in 50 cm ³ of boiling carbon tetrachloride. After 16 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of carbon tetrachloride and dried at 40 ° C under reduced pressure (0.067 kPa). 8.5 g of N - [(2-methoxyethoxy) -7 naphthyridine-1,8 yl-2) 4-methoxy-benzamide] are obtained, melting at 114 ° C.

Amino-2 (methoxy-2 ethoxy) -7 naphthyridine-1,8 can be prepared as follows:

2-methoxy ethanol alcoholate is prepared from 100 cm ³ of corresponding alcohol and 9.2 g of sodium. When the evolution of gas has ceased, 35.9 g of 2-amino-chloro-7, naphthyridine-1,8 are added and the reaction mixture is stirred at 120 ° C. for 2 hours 30 minutes and then poured after cooling into 100 cm ³ of water. The solid obtained is filtered and air dried (30 g; M = 175 ° C). 10 g of product obtained are dissolved in 175 cm ³ of boiling propanol-2. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of propanol-2 and dried at 50 ° C under reduced pressure (0.067 kPa). 8.9 g of amino-2 (2-methoxy-ethoxy) -7-naphthyridine-1.8 are obtained, melting at 176 ° C.

Example 30

The procedure is analogous to that described in Example 1, but starting with 9.6 g of 4-methoxy benzoic acid of 10.2 g of N, N'-carbonyldiimidazole and of 8.5 g of d allyloxy-2 amino-7 naphthyridine-1,8. The product obtained by precipitation in water (13.9 g; mp about 70 ° C) is purified by chromatography on a column 40 mm in diameter containing 250 g of silica (0.040 - 0.063 mm), eluting with a mixture ( 99-1 by volume) of methylene chloride and methanol. Fractions of 100 cm ³ are collected, fractions 9 to 23 are combined and concentrated to dryness at 40 ° C under reduced pressure (4 kPa) to give 10 g of a fatty solid. This product is taken up in 50 cm ³ of isopropyl ether. After 30 minutes of stirring at 20 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of isopropyl oxide and dried at 30 ° C under reduced pressure (0.067 kPa). 8.9 g of N- (allyloxy-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 108 ° C.

Allyloxy-2 amino-7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 29, but starting from 17.9 g of 2-amino-7-chloro-naphthyridine-1,8 of 75 cm ³ of allyl alcohol and of 4.6 g of sodium.

After pouring the reaction mixture into water, 17.6 g of a crystalline solid, melting at 138 ° C., are obtained. 7 g of the product obtained are dissolved in 210 cm ³ of boiling carbon tetrachloride. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of carbon tetrachloride and dried at 50 ° C under reduced pressure (0.067 kPa). 6.4 g of 2-allyloxy-7 amino-naphthyridine-1.8 are obtained, melting at 138 ° C.

Example 31

The procedure is analogous to that described in Example 1, but starting with 11.5 g of 4-methoxy benzoic acid, 12 g of N, N'-carbonyldiimidazole and 10 g of amino- 2 propargyloxy-7 naphthyridine-1,8. The product obtained by precipitation in water (15.3 g; M = 140 ° C) is dissolved in 190 cm ³ of boiling ethanol. After cooling for 3 hours at 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of ethanol and dried at 50 ° C under reduced pressure (0.067 kPa). 10.1 g of N- (propargyloxy-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide, melting at 140 ° C., are obtained.

Amino-2-propargyloxy-7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 29, but starting with 179 g of 2-amino-7-chloro-naphthyridine-1,8 of 750 cm ³ of pro-pargyl alcohol and 46 g of sodium. After precipitation in water, the gum obtained (120 g) is taken up with stirring with 500 cm ³ of isopropyl ether. The solid thus obtained (114.5 g; mp approximately 150 ° C.) is purified by chromatography on a column 50 mm in diameter containing 1 kg of silica (0.063 - 0.2 mm), eluting with methylene chloride and collecting fractions of 100 cm ³ (fractions 11 to 20) then of 500 cm ³ (fractions 21 to 26). After dry concentrations of fractions 6 to 26 under reduced pressure (4 kPa), the residue obtained is washed with stirring in ethyl ether, filtered and then dried. 21 g of a solid, melting at 184 ° C., are obtained. 10.8 g of this product are dissolved in 100 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 6.8 g of amino-2-propargyloxy-7 naphthyridin-1.8 are obtained.

Example 32

The procedure is analogous to that described in Example 1, but starting with 11.8 g of 4-methoxy benzoic acid, 12.6 g of N, N'-carbonyidiimidazole and 9, 6 g of amino-2 methylthio-7 naphthyridine-1,8. The product obtained by precipitation in water (15.8 g; M = 100 ° C) is dissolved in 180 cm ³ of boiling 2-propanol. After 1 hour of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of propanol-2 then with 2 times 10 cm ³ of isopropyl ether and dried at 40 ° C under reduced pressure ( 0.067 kPa). 13.6 g of N- (methylthio-7 naphthyridine-1,8 yl-2) methoxy-benzamide, melting at 130 ° C., are obtained.

Methylthio-1 amino-7 naphthyridine-1,8 can be prepared as follows:

To a solution, close to saturation, of methyl mercaptan in 200 cm ³ of dimethylformamide maintained at 0 ° C., 13.3 g of sodium hydride in 50% suspension in mineral oil are added in small portions. . 25 g of amino-2-chloro-7 naphthyridine-1,8 are then added to this solution and the mixture is heated at 100 ° C. for 2 hours. After cooling, the reaction mixture is poured into 500 cm ³ of water and extracted with 5 times 250 cm ³ of methylene chloride. The organic extracts are then washed with 2 times 200 cm ³ of distilled water, dried over magnesium sulfate and concentrated to dryness at 40 ° C under reduced pressure (4 kPa). The product obtained (22.9 g; M = 130 ° C) is dissolved in 150 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and then 3 times 10 cm ³ of isopropyl ether and dried at 40 ° C under reduced pressure (0.067 kPa). 9.6 g of amino-2 methylthio-7 naphthyridine-1,8, melting at 158 ° C., are obtained.

Example 33

By operating in a manner analogous to that described in Example 1, but starting from 4.1 g of 4-methoxy benzoic acid, 4.4 g of N, N'-carbonyl-diimidazole and 4.75 g of amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (8.8 g) is purified by chromatography on a column 3 cm in diameter containing 140 g of silica (0.063 - 0.2 mm), eluting with a mixture (99-1 by volume) of methylene chloride and ethyl acetate. Fractions of 50 cm ³ are collected, fractions 7 to 20 are combined and concentrated to dryness at 40 ° C under reduced pressure (4 kPa) to give 5.9 g of a solid melting at about 150 ° C. This product is dissolved in 70 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 10 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 160 ° C.

Example 34

The procedure is analogous to that described in Example 1, but starting with 6.1 g of 4-methoxy benzoic acid, 6.5 g of N, N'-carbonyldiimidazole and 7.65 g amino-2 (fluoro-2 phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (5.5 g; M = 200 ° C) is dissolved in 180 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by wire tration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 3.8 g of N - [(2-fluoro phenoxy) -7 naphthyridine-1.8 yl-2] 4-methoxy benzamide, melting at 208 ° C., are obtained.

Amino-2 (fluoro-2 phenoxy) -7 naphthydine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 37, but starting with 18 g of 2-amino-7-chloro-naphthyridin-1,8, 44.8 g of 2-fluoro-phenol and 13.2 g of potash in 85% lozenges. After treatment with sodium hydroxide and washing, the product obtained (24 g; M = 202 ° C) is dissolved in 200 cm ³ of boiling ethanol. After 16 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 15 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 14.9 g of amino-2 (2-fluoro-phenoxy) -naphthyridin-1.8, melting at 206 ° C., are obtained.

Example 35

The procedure is analogous to that described in Example 1, but starting with 6.1 g of 4-methoxy benzoic acid, 6.5 g of N, N'-carbonyldiimidazole and 7.65 g amino-2 (fluoro-3 phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (14 g) is dissolved in 110 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 45 ° C under reduced pressure (0.067 kPa). We obtain 7 g ge N - [(3-fluoro phenoxy) -7 naphthyridin-1,8 yl-2] 4-methoxy benzamide melting at 151 ° C.

Amino-2 (fluoro-3 phenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 37, but starting with 18 g of 2-amino-7-chloro-naphthyridine-1,8, 44,8 g of 3-fluoro-phenol and 13, 2 g of potash in 85% lozenges. After treatment with soda and washing, the product obtained (23.5 g; M = 161 ° C) is dissolved in 120 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 16.5 g of amino-2 (3-fluoro-phenoxy) -7 naphthyridin-1.8, melting at 165 ° C., are obtained.

Example 36

The procedure is analogous to that described in Example 1, but starting with 14.3 g of 4-methoxy benzoic acid, 15.2 g of N, N'-carbonyldiimidazole and 15.2 g amino-2 (4-fluoro phenoxy) -7 naphthyridine-1.8. The product obtained by precipitation in water (22.6 g; mp about 70 ° C) is dissolved in 130 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 15 cm ³ of ethanol and dried at 25 ° C under reduced pressure (0.067 kPa). 17 g of N - [(4-fluoro phenoxy) -7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 100 ° C., are obtained.

Amino-2 (4-fluorophenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting from 17.9 g of 2-amino-7-chloro-naphthyridin-1,8, 44.8 g of fluoro-4phenol and 13 , 2 g potash in 85% lozenges. After 2 hours of heating to 115 ° C. and treatment as described previously in Example 4, 15.2 g of amino-2 (4-fluoro-phenoxy) -7 naphthyridine-1,8 are obtained, melting at 210 ° C.

Example 37

The procedure is analogous to that described in Example 1, but starting from 16.4 g of 4-methoxy benzoic acid, 17.5 g of N, N'-carbonyldiimidazole and 18.5 g amino-2 (2-chloro-phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (28 g; mp about 80 ° C) is dissolved in 800 cm ³ of boiling ethanol. After 15 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 20 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 17.8 g of N - [(2-chloro-phenoxy) -7 naphthyridin-1,8 yl-2] 4-methoxy-benzamide are obtained, melting at 190 ° C.

Amino-2 (2-chloro-phenoxy) -7 naphthyridine-1,8 can be prepared as follows:

A mixture composed of 17.9 g of 3-amino-7-chloro-naphthyridine-1,8, 51.4 g of 2-chloro-phenol and 13.2 g of potash pellets is heated for 4 hours at 120 ° C. 85%. The mixture obtained is poured into 100 cm ³ of 4N sodium hydroxide, the precipitate formed is filtered off and washed with water until pH = 7. After drying at 40 ° C under reduced pressure (0.067 kPa), 20 are obtained. , 6 g of amino-2 (2-chloro-phenoxy) -7 naphthyridin-1,8, melting at 166 ° C.

Example 38

The procedure is analogous to that described in Example 1, but starting with 9.7 g of 4-methoxy benzoic acid, 10.4 g of N, N'-carbonyldiimidazole and 12.4 g amino-2 (2-bromo phenoxy) -7 naphthyridine-1.8. The product obtained by precipitation in water (17.6 g; mp about 70 ° C) is purified by chromatography on a column 45 mm in diameter containing 250 g of silica (0.040 - 0.063 mm), eluting with a mixture ( 99-1 by volume) of methylene chloride and methanol and collecting 50 cm ³ fractions. After concentrating the fractions 5 to 17 to 40 ^° C. to dryness under reduced pressure (4 kPa) to dryness, 10.4 g of a solid melting at approximately 70 ° C. are obtained. This product is dissolved in 270 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 15 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 8.8 g of N - [(2-bromo-phenoxy) -7 naphthyridin-1,8 yl-2) 4-methoxy-benzamide, melting at 183 ° C., are obtained.

Amino-2 (2-bromo-phenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting with 19.7 g of 2-amino-7-chloro-naphthyridin-1.8, 81.5 g of 2-bromo-phenol and 15 , 15 g of potash in 85% lozenges. After 10 hours of heating to 120 ° C and treatment under the conditions described above in Example 4, the product obtained (21.5 g; M = 160 ° C) is purified by chromatography on a column 45 mm in diameter containing 300 g of silica (0.040 - 0.063 mm), eluting with a mixture (95-5 by volume) of methylene chloride and methanol and collecting fractions of 100 cm ³ . After dry concentration of fractions 2 at 10 to 40 ° C under reduced pressure (4 kPa), 12.8 g of amino-2 (2-bromo-phenoxy) -7 naphthyridine-1,8 are obtained, melting at 206 ° C .

Example 39

The procedure is analogous to that described in Example 1, but starting with 15 g of 4-methoxy benzoic acid, 16 g of N, N'-carbonyldiimidazole and 15.6 g of amino- 2 (2-methylphenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (19 g; M = 50 ° C) is purified by chromatography on a column 45 mm in diameter containing 270 g of silica (0.040 - 0.063 mm), eluting with pure dichloromethane. 100 cm ³ fractions are collected. After dry concentration of fractions 3 to 40 under reduced pressure (4 kPa) at 40 ° C, 14 g of a solid melting at approximately 50 ° C are obtained. This product is dissolved in 120 cm ³ of boiling ethanol. After cooling for 4 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 11.1 g of N - [(2-methylphenoxy) -7-naphthyridine-1,8 yl-2] methoxy-4 benzamide are obtained, melting at 153 ° C.

Amino-2 (2-methylphenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting from 17.95 g of 2-amino-7-chloro-naphthyridin-1,8, 43.2 g of 2-methylphenol and 13.2 g of potash in 85% lozenges. After treatment with soda and washing, the product obtained (21.2 g; M = 188 ° C) is dissolved in 100 cm ³ of boiling acetonitrile. After 4 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 15.6 g of amino-2 (2-methylphenoxy) -7 naphthyridin-1.8, melting at 192 ° C., are obtained.

Example 40

The procedure is analogous to that described in Example 1, but starting from 8.5 of 4-methoxy benzoic acid, 9 g of N, N'-carbonyldiimidazole and 9 g of 2-amino (3-methylphenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (10 g; M = 110 ° C) is purified by filtration on a column 45 mm in diameter containing 150 g of silica (0.040 - 0.063 mm), eluting with pure dichloromethane and in collecting fractions of 100 cm ³ . After concentrating the fractions 1 to 30 to 40 ° C to dryness under reduced pressure (4 kPa), 9 g of a solid melting at 158 ° C are obtained. This product is dissolved in 120 cm ³ of boiling ethanol. After cooling for 4 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 7.2 g of N - [(3-methylphenoxy) -7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 160 ° C., are obtained.

Amino-2 (3-methylphenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting from 17.95 g of 2-amino-7-chloro-naphthyridin-1,8, 43.2 g of 3-methylphenol and 13 , 2 g of potash in 85% lozenges. After treatment with sodium hydroxide and washing, the product obtained (21.6 g; M = 148 ° C) is dissolved in 200 cm ³ of boiling ethyl acetate. After cooling for 18 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethyl acetate and dried at 40 ° C under reduced pressure (0.067 kPa). 9 g of amino-2 (3-methylphenoxy) -7 naphthyridin-1.8, melting at 152 ° C., are obtained.

Example 41

The procedure is analogous to that described in Example 1, but starting with 16.7 g of 4-methoxy benzoic acid, 17.8 g of N, N'-carbonyldiimidazole and 21.2 g amino-2 (2,6-dimethyl phenoxy) -7 naphthyridine-1,8. The reaction mixture is poured into water and extracted with methylene chloride. After concentrating the organic phases to dryness under reduced pressure (4 kPa), the solid residue (33 g) is dissolved in 170 cm ³ of boiling acetone. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of acetone and dried at 40 ° C under reduced pressure (0.067 kPa). By recrystallization of the solid obtained (11.5 g; mp about 100 ° C.) in 50 cm ³ of acetone, 9.1 g of N - [(2,6-dimethylphenoxy) -7 naphthyridine-1,8 yl are obtained. -2) 4-methoxy benzamide melting at 174 ° C.

Amino-2 (2,6-dimethylphenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting from 17.95 g of 2-amino-7-chloro-naphthyridin-1,8, of 48.6 g of 2,6-dimethylphenol and 13.2 g of potash in 85% lozenges. After treatment with sodium hydroxide and washing, the product obtained (24.8 g; M = 204 ° C) is purified by chromatography on a column 45 mm in diameter, containing 360 g of silica (0.040 - 0.063 mm), eluting with pure methylene chloride and collecting 100 cm ³ fractions. After dry concentration of fractions 1 to 48 at 40 ° C under reduced pressure (4 kPa), 21.2 g of amino-2 (2,6-dimethylphenoxy) -7 naphthyridine-1,8 are obtained, melting at 218 ° C.

Example 42

The procedure is analogous to that described in Example 1, but starting with 10.2 g of 4-methoxy benzoic acid, 10.9 g of N, N'-carbonyldiimidazole and 13.4 g amino-2 (2-methoxy phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (18 g; M = 167 ° C) is dissolved in 400 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 45 ° C under reduced pressure (0.067 kPa). 14 g of N - [(2-methoxyphenoxy) -7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 168-170 ° C., are obtained.

Example 43

The procedure is analogous to that described in Example 1, but starting with 15.9 g of 4-methoxy benzoic acid, 17 g of N, N'-carbonyldiimidazole and 17.7 g of amino-2 (3-methoxy phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (12.1 g, mp = 148 ° C) is purified by filtration on a column 45 mm in diameter containing 180 g of silica (0.040 - 0.063 mm), eluting with pure dichloromethane and collecting 100 cm ³ fractions ^. After dry concentration of fractions 1 to 50 at 40 ° C under reduced pressure (4 kPa), 10 g of a solid melting at 148 ° C are obtained. This product is dissolved in 130 cm ³ of boiling ethanol. After cooling for 18 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 9 g of N - [(3-methoxyphenoxy) -7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 150 ° C., are obtained.

Amino-2 (3-methoxyphenoxy) -7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting with 17.95 g of 2-amino-7-chloro-naphthyridin-1,8, 49.6 g of 3-methoxyphenol and 13.2 g of potash in 85% lozenges. After treatment with sodium hydroxide and washing, the product obtained (23.8 g; M = 156 ° C) is dissolved in 200 cm ³ of boiling ethanol. After cooling for 18 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 17.7 g of amino-2 (3-methoxy-phenoxy) -naphthyridin-1.8, melting at 160 ° C., are obtained.

Example 44

The procedure is analogous to that described in Example 1, but starting with 9.5 g of 4-methoxy benzoic acid, 10.2 g of N, N'-carbonyldiimidazole and 10.7 g amino-2 (4-methoxy phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (14.3 g; M = 106 ° C) is purified by chromatography on a column 35 mm in diameter containing 200 g of silica (0.040 - 0.063 mm), eluting with a mixture ( 98-2 by volume) of methylene chloride and methanol and collecting 50 cm ³ fractions. Fractions 22 to 28 are concentrated to dryness under reduced pressure (4 kPa) to give 10.8 g of a solid melting at 150 ° C. This product is dissolved in 250 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 9 g of N - [(4-methoxyphenoxy) -7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 163 ° C., are obtained.

Example 45

The procedure is analogous to that described in Example 1, but starting with 3.6 g of 4-methoxy benzoic acid, 4.05 g of N, N'-carbonyldiimidazole and 6.5 g amino-2 (pyridyl-3) oxy-7 naphthyridine-1,8. The product obtained by precipitation in water (3.9 g; mp about 110 ° C.) is purified by chromatography on a column 25 mm in diameter containing 80 g of silica (0.040 - 0.063 mm), eluting with methylene and collecting 50 cm ³ fractions. Fractions 16 to 28 are combined and concentrated to dryness under reduced pressure (4 kPa) to yield 3.2 g of crystalline solid, melting at 174 ° C. The isolated product is dissolved in 125 cm ³ of boiling ethyl acetate. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 3 cm ³ of ethyl acetate and dried at 50 ° C under reduced pressure (0.067 kPa). 2.5 g of N - [(pyridyl-3) oxy-7 naphthyridin-1,8 yl-21 4-methoxy-benzamide, melting at 184 ° C., are obtained.

Amino-2 (pyridyl-3) oxy-7 naphthyridine-1,8 can be prepared as follows:

The procedure is analogous to that described in Example 4, but starting with 17.9 g of 2-amino-7-chloro-naphthyridin-1,8, 38 g of 3-hydroxy pyridine and 11 , 2 g of potash in 85% lozenges. The product obtained by precipitation in water and extraction with ethyl acetate (4.7 g) is dissolved in 80 cm ³ of boiling ethyl acetate. After 3 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 5 cm ³ of ethyl ether and air dried at 20 ° C. 2.1 g of amino-2 (pyridyl-3) oxy-7 naphthyridin-1.8 are obtained, melting at 178 ° C.

Example 46

The procedure is analogous to that described in Example 1, but starting with 4.6 g of 4-methoxy benzoic acid, 4.9 g of N, N'-carbonyidiimidazole and 5.1 g amino-2 (1-methyl-piperidyl-4) oxy-7 naphthyridin-1,8. The product obtained by precipitation in water (6.5 g; F about 80 ° C) is dissolved in 100 cm ³ of methylene chloride, the product is extracted with 100 cm ³ of 2N hydrochloric acid, the aqueous phase obtained is washed with 2 times 50 cm ³ of methylene chloride and neutralized with 50 cm ³ of 4N sodium hydroxide in the presence of 100 cm ³ of methylene chloride. After washing with water and drying, the organic phase is concentrated to dryness at 40 ° C under reduced pressure (4 kPa) to give 6.3 g of an amorphous product. This product is dissolved in 50 cm ³ of boiling methylcyclohexane. After 1 hour of cooling to 20 ° C, the crystallized solid is separated by filtration, washed with 20 cm ³ of methylcyclohexane and dried at 50 ° C under reduced pressure (0.067 kPa). 5.6 g of N - [(2-methyl-piperidyl-4) oxy-7 naphthyridine-1,8 yl-21 methoxy-4 benzamide, melting at 200 ° C., are obtained.

Amino-2 (1-methyl-piperidyl-4) oxy-7 naphthyridin-1, 8 can be prepared as follows:

The procedure is analogous to that described in Example 29, but starting from 27 g of 2-amino-7-chloro-naphthyridine-1,8 of 71 g of 4-hydroxy-1-methyl-piperidine and 8 g of sodium. After treatment with water, the reaction mixture is extracted with methylene chloride to give 33.4 g of an amorphous solid. This solid is purified by chromatography on a column 60 mm in diameter containing 335 g of silica (0.040 - 0.063 mm), eluting with a mixture (90-10 by volume) of methylene chloride and methanol and collecting fractions of 100 cm ³ . Fractions 12 to 35 are con dry centered under reduced pressure (4 kPa) to give 10.4 g of a solid melting approximately at 100 ° C. This product is dissolved in 50 cm ³ of boiling cyclohexane. After cooling for 1 hour at 4 ° C., the crystallized solid is separated by filtration, washed with 20 cm ³ of cyclohexane and dried at 40 ° C under reduced pressure (0.067 kPa). 4.3 g of amino-2 (1-methyl-piperidyl-4) oxy-7 naphthyridine-1.8 are obtained, melting at 174 ° C.

Example 47

The procedure is analogous to that described in Example 1, but starting with 13.3 g of 4-ethoxy-benzoic acid, 12.9 g of N, N'-carbonyldiimidazole and 8.9 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (15.3 g; mp approximately 170 ° C) is dissolved in 500 cm ³ of boiling acetonitrile. After cooling for 16 hours at 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 25 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa).

8 g of N- (chloro-7 naphthyridine-1,8 yl-2) ethoxy-4 benzamide are obtained, melting at 208 ° C.

Example 48

The procedure is analogous to that described in Example 1, but starting with 8 g of 4-ethoxy benzoic acid, 7.8 g of N, N'-carbonyldiimidazole and 5.6 g of 2-amino-7-methoxy-naphthyridine-1,8. The product obtained by precipitation in water (9.4 g; M = 74 ° C) is dissolved in 94 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of acetonitrile and dried at 30 ° C under reduced pressure (0.067 kPa). 7 g of N- (7-methoxy-naphthyridine-1,8 yl-2) ethoxy-4 benzamide are obtained, melting at 145 ° C.

Example 49

The procedure is analogous to that described in Example 1, but starting with 15.5 g of 4-butoxy benzoic acid, 12.9 g of N, N'-carbonyldlimidazole and 8.9 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (about 18 g; M = 140 ° C) is purified by chromatography on a column 40 mm in diameter loaded with 200 g of silica (0.063 - 0.2 mm) using as eluent methylene chloride and collecting 60 cm ³ fractions ^. After dry concentration of fractions 8 to 12 at 40 ° C under reduced pressure (4 kPa), 6.2 g of N- (7-chloro-naphthyridine-1) are obtained. , 8 yl-2) 4-butoxy-benzamide melting at 197 ° C.

Example 50

The procedure is analogous to that described in Example 1, but starting with 16.6 g of 3,4-methylenedioxy-benzoic acid, 16.2 g of N, N'-carbonyldiimidazole and 11, 7 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (15.7 g; M = 256 ° C) is dissolved in 1000 cm ³ of propanol-1. After cooling for 16 hours at 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of propanol-1 and dried at 40 ° C under reduced pressure (0.067 kPa). 8.4 g of N- (7-chloro-naphthyridine-1,8 yl-2)-3,4-methylenedioxy benzamide are obtained, melting at 256 ° C.

Example 51

The procedure is analogous to that described in Example 1, but starting with 6.6 g of 3-dimethylamino benzoic acid, 6.5 g of N, N'-carbonyldiimidazole and 5.4 g amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (9 g; M = 212 ° C) is dissolved in 400 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 6.2 g of N- (7-chloro-naphthyridine-1,8 yl-2) dimethylamino-3 benzamide are obtained, melting at 215 ° C.

Example 52

The procedure is analogous to that described in Example 1, but starting with 18.6 g of 3-dimethylamino benzoic acid, 17.8 g of N, N'-carbonyldiimidazole and 12.3 g amino-2 methoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (24.7 g; M = 82-84 ° C) is purified by chromatography on a column 4.5 cm in diameter containing 220 g of silica (0.040 - 0.063 mm), eluting with a mixture (98-2 by volume) of dichloromethane and methanol. Fractions of 100 cm ³ are collected, fractions 7 to 22 are combined and concentrated at 40 ° C under reduced pressure (4 kPa) to give 24 g of a solid melting at 90 ° C. This product is dissolved in 120 cm ³ of boiling acetonitrile. After 1 hour of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of isopropyl ether and dried at 40 ° C under reduced pressure (0.5 mm of mercury). 5.7 g of N- (7-methoxy-naphthyridine -1.8 yl-2) dimethylamino-3 benzamide are obtained, melting at 130 ° C.

Example 53

By following a procedure analogous to that described in Example 1, but starting with 23.1 g of 3-dimethylamino benzoic acid, 22.7 g of N, N'-carbonyldiimidazole and 23.7 g amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (44 g; mp about 90 ° C) is dissolved in 1000 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 50 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 32 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) dimethylamino-3 benzamide are obtained, melting at 120 ° C.

Example 54

The procedure is analogous to that described in Example 1, but starting with 3.7 g of nicotinic acid, 4.9 g of N, N'-carbonyldiimidazole and 3.6 g of amino -2 chloro-7 naphthyridine-1,8. The product precipitated from the mixture is separated by filtration, washed with 3 times 20 cm ³ of tetrahydrofuran, 3 times 50 cm ³ of water and is then dried at 50 ° C under reduced pressure (0.067 kPa). The product obtained (4.75 g; M = 200 ° C) is dissolved in 435 cm3 of boiling acetonitrile. After 2 hours of cooling to 4 ° C the crystallized solid is separated by filtration, washed with 3 times 20 cm ³ of acetonitrile and dried at 50 ° C under reduced pressure (0.067 kPa). Obtained 3.9 g of N- (chloro-7 naphthyridine-1,8 yl-2) pyridylcarboxamide-3 melting at 200 ° C.

Example 55

The procedure is analogous to that described in Example 1, but starting from 7.4 g of nicotinic acid, 9.7 g of N, N'-carbonyldiimidazole and 7 g of 2-amino methoxy -7 naphthyridine-1.8. After filtration, washing with water and drying, the crystalline solid formed during the reaction (10.3 g; M = 245 ° C) is dissolved in 900 cm ³ of boiling propanol-1. The solid crystallized after 3 hours of cooling to 40 ° C. is separated by filtration, washed with 3 times 20 cm ² of propanol-1 and dried at 50 ° C. under reduced pressure (0.067 kPa). 8.7 g of N- (7-methoxy-naphthyridine-1,8 yl-2) pyridylcarboxamide-3 are obtained, melting at 247 ° C.

Example 56

The procedure is identical to that described in Example 1, but starting with 1.7 g of 6-methoxy-3-pyridine carboxylic acid, 1.8 g of N, N'-carbonyl-diimidazole and 1.95 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained (2.5 g; M = 270 ° C) is dissolved in 190 cm ³ of a dimethylformamide methanol mixture (1/6).

After 1 hour of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of methanol and dried at 40 ° C under reduced pressure (0.066 kPa). 2.1 g of N- (chloro-7 naphthyridine-1,8 yl-2) methoxy-6 pyridinecarboxamide-3 are obtained, melting at 270 ° C.

6-methoxy-pyridinecarboxylic-3 acid can be prepared as follows:

To a suspension of 4.15 g of 6-chloro-pyridinecarboxylic-3 acid in 40 cm ³ of methanol, 40 cm ³ of a 4M methanolic solution of sodium methylate are added. The mixture is heated at reflux for 60 hours. The solvent is distilled under reduced pressure (4 kPa). The residue is taken up in 100 cm ³ of distilled water, and the mixture is acidified to pH 5 with hydrochloric acid in 11.9M aqueous solution. The precipitate obtained is separated by filtration, washed with 5 times 10 cm ³ of distilled water and air dried. 3.3 g of 6-methoxy-3-pyridinecarboxylic acid are obtained, melting at 180 ° C.

Example 57

The procedure is analogous to that described in Example 1, but starting with 4.7 g of 6-methoxy-pyridinecarboxylic-3 acid, 4.9 g of N, N'-carbonyidiimidazole and 9.1 g of amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (11 g; M = 115 ° C) is dissolved in 50 cm ³ of boiling acetonitrile. After cooling for 10 hours at 20 ° C., the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of diisopropylether and dried at 30 ° C under reduced pressure (0.067 kPa). 7 g of N- (phenoxy-7 naphthyridine-1,8 yl-2 methoxy-6 pyridinecarboxamide-3, melting at 115-120 ° C., are obtained.

Example 58

The procedure is analogous to that described in Example 1, but starting with 9 g of thiophene-carboxylic acid-2, 11.3 g of N, N'-carbonyidiimidazole and 9.5 d of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (9.6 g; M = 242 ° C) is dissolved in 700 cm ³ of boiling ethanol. After 1 hour of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 25 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 7.5 g of N- (chloro-7 naphthyridine-1,8 yl-2) thiophenecarboxamide-2, melting at 244 ° C., are obtained.

Example 59

The procedure is analogous to that described in Example 1, but starting from 16 g of thiophene-carboxylic-3 acid, 20.1 g of N, N'-carbonyldiimidazole and 16.8 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (10.6 g; M = 250 ° C) is dissolved in 980 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 25 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 7.5 g of N- (chloro-7 naphthyridine-1,8 yl-2) thiophenecarboxamide-3, melting at 254 ° C., are obtained.

Example 60

The procedure is analogous to that described in Example 1, but starting with 14 g of 2-thiophene carboxylic acid, 17.8 g of N, N'-carbonyl-diimidazole and 12, 3 g of amino-2 methoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (19.5 g; M = 216 ° C) is dissolved in 750 cm ³ of boiling ethanol. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 25 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 15.6 g of N- (7-methoxy-naphthyridine-1,8 yl-2) thiophenecarboxamide-2 are obtained, melting at 220 ° C.

Example 61

The procedure is analogous to that described in Example 1, but starting with 4 g of thiophene-2-carboxylic acid, 5.1 g of N, N'-carbonyldiimidazole and 7 g of 'amino-2-chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (8.8 g; mp 175 ° C) is dissolved in 150 cm ³ of boiling methanol. After cooling for 3 hours at 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of methanol and dried at 40 ° C under reduced pressure (0.067 kPa). 6 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) thiophenecarboxamide-2, melting at 176 ° C., are obtained.

Example 62

The procedure is analogous to that described in Example 1, but starting with 5 g of thiophene-carboxylic-3 acid, 6.3 g of N, N'-carbonyldiimidazole and 8.3 g of amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (11.6 g; mp = 110 ° C.) is dissolved in 50 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 10 cm ³ of diisopropyl ether and dried at 35 ° C under reduced pressure (0.067 kPa). 8.2 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) thiophenecarboxamide-3, melting at 95 ° C., are obtained.

Example 63

The procedure is identical to that described in Example 1, but starting with 4.1 g of 5-methyl-thiophenecarboxylic acid _- 2, 5.6 g of N, N'-car-bonyldiimidazole and 4.85 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained (3.8 g; M = 220 ° C) is dissolved in 150 cm ³ of boiling acetonitrile. After 4 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.066 kPa). 3.1 g of N- (chloro-7 naphthyridine-1,8 yl-2) methyl-5 thiophenecarboxamide-2, melting at 222 ° C., are obtained.

Example 64

The procedure is analogous to that described in Example 1, but starting from 8.95 g of furan-carboxylic acid-2, 12.8 g of N, N'-carbonyldlimidazole and 10 , 5 g of amino-2-methoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (15.5 g; M = 199 ° C) is dissolved in 500 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of ethanol and dried at 45 ° C under reduced pressure (0.067 kPa). 13.5 g of N- (7-methoxy-naphthyridine-1,8 yl-2) furanecarboxamide-2 are obtained, melting at 201 ° C.

Example 65

The procedure is analogous to that described in Example 1, but starting from 7.5 g of furan-carboxylic-2 acid, 10.9 g of N, N'-carbonyldiimidazole and 11 , 9 g of amino _- 2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (15.7 g; mp = 164 ° C) is dissolved in 200 cm ³ of boiling ethanol. After 2 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 15 cm ³ of ethanol and dried at 40 ° C under reduced pressure (0.067 kPa). 14.4 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) furanecarboxamide-2 are obtained, melting at 167 ° C.

Example 66

The procedure is analogous to that described in Example 1, but starting from 7.5 g of 3-furan carboxylic acid, 10.9 g of N, N'-carbonyldiimidazole and 11.9 g amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water (13g; F approximately 90 ° C) is dissolved in 80 cm ³ of boiling acetonitrile. After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 2 times 10 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 10.7 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) furanecarboxamide-3 are obtained, melting at 102 ° C.

Example 67

To a solution of 12 g of 6-methyl-3-pyridazine carboxylic acid in 250 cm ³ of anhydrous tetrahydrofuran, 20 g of N, N'-carbonyldiimidazole are added. There is a slow release of gas. The mixture is stirred at a temperature in the region of 20 ° C. until gas evolution is completed. 11 g of amino-2-chloro-7 naphthyridine-1,8 are then added and the mixture is heated at reflux for 20 hours. The precipitate obtained is separated by filtration, washed with ethanol, air dried and then extracted with 1000 cm ³ of isopropanol at reflux in a solid-liquid extractor for 20 hours. After 2 hours of cooling to 4 ° C of the isopropanolic solution thus obtained, the crystallized solid is separated by filtration and then dissolved in 300 cm ³ of hot dimethylformamide (120 ° C).

After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 20 cm ³ of methanol and dried at 40 ° C under reduced pressure (0.066 kPa). 4.5 g of N- (7-chloro-naphthyridine-1,8 yl-2) -methyl-6 pyridazinecarboxamide-3, melting at 258 ° C., are obtained.

Example 68

The procedure is analogous to that described in Example 8, but starting with 10.7 g of 2-amino-7-chloro-quinoline in 120 cm ³ of anhydrous pyridine and 15.5 g of benzoyl chloride . The product obtained by precipitation in water (16 g; M = 127 ° C) is isolated by filtration and then dissolved in 1000 cm ³ of boiling cyclohexane. After 1 hour of cooling to 4 ° C, the crystallized solid is separated by filtration and dried at 45 ° C under reduced pressure (0.067 kPa). 12.9 g of a product melting at 130 ° C. are obtained which is again crystallized from 60 cm ³ of boiling acetone. After 1 hour of cooling to 4 ° C, the recrystallized solid is separated by filtration, washed with 2 times 5 cm ³ of acetone and dried at 40 ° C under reduced pressure (0.067 kPa). 9 g of N- (7-chloro-2-quinolyl) benzamide are obtained, melting at 133 ° C.

Example 69

To a solution of 6.65 g of N- (7-formyl-naphthyridine-1,8 yl-2) 4-methoxy benzamide in 150 cm ³ of methanol, 0.41 g is added in 15 minutes, at 20 ° C. sodium borohydride and then allowed to stir for 1 hour at 20 ° C until the end of gas evolution. The suspension obtained is poured onto 800 cm ³ of distilled water which is acidified to pH = 4 with acetic acid. The solid obtained by filtration and drying (6.15 g; M = 212 ° C) is dissolved in 180 cm ³ of boiling dioxane. After cooling for 3 hours to a temperature in the region of 20 ° C, the crystallized solid is separated by filtration, washed with 2 times 15 cm ³ of dioxane and dried at 50 ° C under reduced pressure (0.067 kPa). 4.4 g of N- (7-hydroxymethyl-naphthyridin-1.8 yl-2) 4-methoxy benzamide, melting at 218 ° C., are obtained.

N- (7-formyl-naphthyridine-1,8 yl-2) 4-methoxy benzamide can be prepared as follows:

To a solution of 29.3 g of N- (methyl-7 naphthyridine-1,8 yl-2) methoxy-3 benzamide in 1000 cm ³ of dioxane, 33.1 g of selenium oxide is added and then heated for 3 hours at reflux. The suspension obtained is filtered hot, the filtrate is taken up in 2500 cm ³ of methylene chloride and washed with 5 times 1000 cm ³ of distilled water. The solution organic is dried and concentrated to dryness under reduced pressure (4 kPa) to give 11.1 g of a product melting at 190 ° C. which is dissolved in 500 cm ³ of boiling acetonitrile. After cooling for 2 hours at 4 ° C, the crystallized solid is separated by filtration, washed with 2 times 25 cm ³ of acetonitrile and dried at 50 ° C under reduced pressure (0.06.7 kPa). 6.65 g of N- (7-formyl-naphthyridine-1,8 yl-2) 4-methoxy benzamide are obtained, melting at 194 ° C.

Example 70

To a solution of 15 g of 2-chloro-phenoxycarbonylamino-7 naphthyridine-1,8 in 500 cm ³ of anhydrous tetrahydrofuran, 500 cm ³ of anhydrous acetonitrile and 4.2 g of tetrahydro-1,2,5,6 are added pyridine. The mixture is heated at reflux for 45 minutes. The solution is concentrated under reduced pressure (4 kPa) to a volume of 100 cm ³ . After 2 hours of cooling to 4 ° C., the crystallized solid is separated by filtration, washed with 3 times 15 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 10.5 g of N- (7-chloro-naphthyridine-1,8 yl-2) tetrahydro-1,2,5,6 pyridinecarboxamide-1 are obtained, obtained at 173 ° C.

2-Chloro-phenoxycarbonylamino-7 naphthyridine-1,8 can be prepared as follows:

To a solution of 9.2 g of 2-amino-7-chloro-naphthyridine-1,8 in 130 cm ³ of pyridine, maintained at a temperature in the region of 20 ° C., 9.6 g of chloroformate of phenyl. The mixture is stirred for 3 hours at a temperature in the region of 20 ° C. The mixture is poured into 1000 cm ³ of distilled water. The precipitate formed is separated by filtration and washed with water.

The product obtained (25 g; mp about 200 ° C) is dissolved in 500 cm ³ of boiling acetonitrile. After 3 hours of cooling to 4 ° C, the crystallized solid is separated by filtration, washed with 3 times 50 cm ³ of acetonitrile and dried at 40 ° C under reduced pressure (0.067 kPa). 7.4 g of 2-chloro-phenoxycarbonylamino-7-naphthyridin-1.8, melting at 208 ° C., are obtained.

The present invention also relates to pharmaceutical compositions which contain the products of formula (1) in the pure state or in combination with a compatible and pharmaceutically acceptable adjuvant, diluent and / or coating. These drugs can be used orally, rectally, parenterally or percutaneously.

As solid compositions for oral administration, tablets, pills, powders (generally in gelatin capsules) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

The components according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

The compositions for percutaneous administration are creams, ointments, lotions and liniments, in which the active product is combined with liquid or pasty excipients, preferably in combination with a vehicle promoting percutaneous migration.

The medicaments and compositions according to the invention are particularly useful in human therapy for their anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant action and, if necessary, for their anti-infectious and immunorestorative action.

In human therapy, the doses depend on the desired effect and on the duration of the treatment; they are generally between 10 and 500 mg per day orally for an adult.

In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

The following examples, given without limitation, illustrate a composition according to the invention.

Example A

• - N-chloro-7 naphtyridine-1,8 yl-2) méthoxy-4 benzamide 0,010 g
• - amidon 0,200 g
• - silice précipitée 0,036 g
• - stéarate de magnesium 0,004 g

Tablets containing 10 mg of active product having the following composition are prepared according to the usual technique:

• - N-chloro-7 naphthyridine-1,8 yl-2) 4-methoxy benzamide 0.010 g
• - starch 0.200 g
• - precipitated silica 0.036 g
• - magnesium stearate 0.004 g

Example B

• - N-(chloro-7 naphtyridine-1,8 yl-2) fluoro-4 benzamide 0,010 g
• - amidon 0,200 g
• - silice précipitée 0,036 g
• - stéarate de magnésium 0,004 g

Tablets containing 10 mg of active product having the following composition are prepared according to the usual schedule.

• - N- (chloro-7 naphthyridine-1,8 yl-2) fluoro-4 benzamide 0.010 g
• - starch 0.200 g
• - precipitated silica 0.036 g
• - magnesium stearate 0.004 g

Example C

• - N-(méthoxy-7 naphtyridine-1,8 yl-2) cyclopropanecarboxamide 0,010 g
• - amidon 0,200 g
• - silice précipitée 0,036 g
• - stéarate de magnésium 0,004 g

Tablets containing 10 mg of active product having the following composition are prepared according to the usual technique:

• - N- (7-methoxy-naphthyridine-1,8 yl-2) cyclopropanecarboxamide 0.010 g
• - starch 0.200 g
• - precipitated silica 0.036 g
• - magnesium stearate 0.004 g

Example D

• - N-(méthoxy-7 naphtyridine-1,8 yl-2) thiophènencarboxamide-2 0,010 g
• - amidon 0,200 g
• - silice précipitée 0,036 g
• - stéarate de magnésium 0,004 g

Tablets containing 10 mg of active product having the following composition are prepared according to the usual technique:

• - N- (7-methoxy-naphthyridine-1,8 yl-2) thiophenencarboxamide-2 0.010 g
• - starch 0.200 g
• - precipitated silica 0.036 g
• - magnesium stearate 0.004 g

Claims (9)

1. A substituted amide derivative, characterized in that it corresponds to the general formula:

in which the symbol R denotes a cycloalkyl radical containing 3 to 6 carbon atoms, a cyclohexadienyl or phenyl radical, or a phenyl radical substituted with 1 or 2 fluorine atoms or with a hydroxy radical, or substituted at the 3- or 4-position with an alkyl or alkyloxy radical, or at the 3- and 4-positions with a methylenedioxy radical, or substituted at the 2- or 3-position with a dialkylamino radical, or alternatively the symbol R denotes a heterocyclic radical chosen from 3-pyridyl, alkyloxy-3_-pyridyl, thienyl, alkylthienyl, furyl, tetrahydropyridyl, pyridazinyl and alkylpyridazinyl, and the symbol Het denotes a 2-quinolyl or 1,8-naphthyridin-2-yl radical optionally substituted at the 7-position with a halogen atom, with a hydroxymethyl radical, with an alkyl, alkyloxy or alkyloxyalkyloxy radical, with an alkenyloxy or alkynyloxy radical containing 3 or 4 carbon atoms, with an alkylthio or benzylthio radical, with a phenoxy radical (optionally substituted with a fluorine atom or substituted with a chlorine or bromine atom at the 2-position, or substituted with an alkyloxy radical or with 1 or 2 alkyl radicals), or with a pyridyloxy or alkylpiperidyloxy radical, with the proviso that, when Het denotes a 2-quinolyl radical, R is other than phenyl, and that the alkyl radicals and portions mentioned above are straight or branched and contain 1 to 4 carbon atoms.

2. An amide derivative according to claim 1, in which the symbol R is a cyclopropyl, cyclobutyl, 1,4-cvclohexadien-1-vl or phenyl radical, or a phenyl radical substituted with 1 or 2 fluorine atoms or with a hydroxy radical, or substituted at the 3- or 4-position with an alkyl radical containing 1 or 2 carbon atoms or an alkyloxy radical containing 1 to 4 carbon atoms, or at the 3- end 4-positions with a methylenedioxy radical or substituted with a dimethylamino radical at the 3-position, or alternatively the symbol R is a heterocyclic radical chosen from 3-pyridyl, 6-alkyloxy-3-pyridyl, thienyl, 5-alkylthienyl, furyl, 3-pyridazinyl or 6-alkyl-3-pyridazinyl in which the alkyl portions contain 1 or 2 carbon atoms, and the symbol Het denotes a 2-quinolyl or 1,8-naphthyridin-2-yl radical optionally substituted at the 7-position with a halogen atom, with a hydroxymethyl radical, with an alkyl or alkylthio radical containing 1 or 2 carbon atoms, with an alkyloxy radical containing 1 to 4 carbon atoms or an alkyloxyalkyloxy radical containing 2 to 4 carbon atoms, with an allyloxy, propargyloxy or benzylthio radical, with a phenoxy radical (optionally substituted with a fluorine atom or with a chlorine or bromine atom at the 2-position, with an alkyloxy radical or with 1 or 2 alkyl radicals containing 1 or 2 carbon atoms) or with a 3-pyridyloxy or 1-alkyl-4-piperidyl- oxy radical, with the proviso that, when the symbol Het denotes a 2-quinolyl radical, R is other than phenyl.

3. An amide derivative according to claim 1, in which the symbol R is a cyclopropyl, 1,4-cyclo- hexadien-1-yl or phenyl radical, or a phenyl radical substituted with 1 or 2 fluorine atoms or with a hydroxy radical, or substituted at the 3- or 4-position with an alkyloxy radical containing 1 or 2 carbon atoms or at the 3- and 4-positions with a methylenedioxy radical, or substituted at the 3-position with a dimethylamino radical, or alternatively the symbol R is a heterocyclic radical chosen from 3-pyridyl, 6-alkyloxy-3-pyridyl in which the alkyl portion contains 1 or 2 carbon atoms, thienyl or furyl, and the symbol Het denotes a 1,8-naphthyri- din-2-yl radical optionally substituted at the 7-position with a halogen atom, with an alkyl, alkyloxy or alkylthio radical containing 1 or 2 carbon atoms, with an alkyloxyalkyloxy radical containing 2 to 4 carbon atoms, with an allyloxy or phenoxy radical (optionally substituted with a fluorine atom, or with a chlorine or bromine atom at the 2-position, with an alkyloxy radical or with 1 or 2 alkyl radicals containing 1 or 2 carbon atoms), or with a 3-pyridyloxy radical.

4. An amide derivative according to claim 1, in which the symbol R is a cyclopropyl or phenyl radical or a phenyl radical substituted at the 3- or 4-position with a fluorine atom, or substituted with 2 fluorine atoms or with a hydroxy radical, or substituted at the 3- or 4-position with a methoxy radical, or alternatively the symbol R is a heterocyclic radical chosen from 6-alkyloxy-3-pyridyl in which the alkyl portion contains 1 or 2 carbon atoms, 2-thienyl or 3-furyl, and the symbol Het denotes a 1,8-naphthyridin-2-yi radical substituted at the 7-position with a halogen atom, with a methoxy radical or with a phenoxy radical (optionally substituted with a fluorine atom or at the 2-position with a chlorine atom or a methyl radical, or at the 2-or 3-position with a methoxy radical), or the symbol R denotes a 1,4-cyciohexadien-l-yi radical, a phenyl radical (substituted at the 3- and 4-positions with a methylenedioxy radical or substituted at the 3-position with a dimethylamino radical) or a 3-pyridyl radical, and the symbol Het denotes a 1,8-naphthyridin-2-yl radical substituted at the 7-position with a halogen atom.

5. A process for preparing a product according to claim 1, wherein an acid of general formula:

in which R is defined as in claim 1, or a reactive derivative of this acid, is reacted with an amine of general formula:

in which Het is defined as in claim 1, and then, where appropriate, the protective radicals are removed.

6. A process according to claim 2, wherein a reactive derivative of the acid, chosen from the acid anhydride, a mixed anhydride, an acid halide or an ester, is reacted.

7. A process for preparing a product according to claim 1, for which the symbol Het contains a hydroxymethyl substituent, wherein the corresponding aldehyde is reduced.

8. A process for preparing a product according to claim 1, for which the symbol R is a tetrahydropyridyl radical, wherein tetrahydropyridine is reacted with a carbamate of general formula:

in which the symbol Het is defined as in Claim 1.

9. A pharmaceutical composition, which comprises at least one product according to claim 1, in the pure state or in combination with any other diluent or adjuvant which is compatible and pharmaceutically acceptable.